Aromatic mercury salts of acetylamino substituted acids



Patented Aug. 1, 1939 PATENT o-FFI-cE AitoMATIo MERCURY sAL'rs or AoE'rYL- AMINO- SUBSTITUTED ACIDS G'arlN. Andersen, wellesley mod ms, assignor Maine to Lever Brothers Company, a corporation of No easing; Appli'cation November 17, 1936, Scrial'No. 111,255

\ 13 Claims (01. 250-434) The present invention-relates to certain new: aromatic mercury salts of acetylamino substituted acids.

It is an-objectof my invention to produce such new organic mercury; compounds usefullas germicides and for othentherapeuticpurposes.

I havediscovered that whenjthe hydrogen atom; of an acidic group or groups in an acetylamino:

substituted acidis'replaced bythe essential radical.

of certain aromatic mercury comp,ounds;.com@ pounds are produced which have. extraordinarily high potencytas antiseptics and germicides and at the same time are characterized .byrelatively low toxicity and other desirable properties.

The compounds I have produced may be described as having the generaliormula (RHg)m.R1, in which R. represents an aromatic structure to a carbon atom of which the mercury is directly attached; in which R1 represents an acetylamino substitutedacid radical'that is linked to the RHg groupor groups through the replacement of the hydrogen atom ofthe' acidic groupor groups; and in which it represents the number of RHg groups in' the compound and is an integer of at leastone andnotmore th'an'the numberof acid-ic' hydrogens in the acetylamino substitutedacid;

While the words group and groups are used hereinafter, it will be understood that these words must be interpreted-as single or plural depending upon the value of a3.

More particularly, R'rep'resents an aromatic structure, which may be an aromatic nucleus with j or 'withoutside chains, and the expression aro matic structure used herein isintendedto be generic and include an aromatic nucleus with or without side chains. of the type in which none oithe nuclear'or side chain carbon atoms has directlinkage with any element other than hydrogen, carbon or mercury.

40 R may stand for any mono or polycyclic hydro carbon group in which all of the nuclear carbon atoms, other than the one attached to mercury, and any side chain carbon atoms, have their valences satisfied either by carbon or hydrogen.

Examples are the phenyl, diphenyl, tolyl, .xylyl and naphthyl groups.

'R1 represents the radical of any acetylamino I substituted acid, i. e., an acid containing the group -NHCOCI-I3 which is substituted for hydrogen. The acids may be either aliphatic or The aromatic structure is acidic group or groups and the acetylamino group or groups may be attached to the same or different nuclei. Saturated or unsaturated side chains may be attached to a cyclic nucleus-and the acid radical or acetylaminoradical may be 5 attached to either the side chin or the nucleus. Groupsother than the acetylamino groupmay be substituted in the acid, for example,- the halogens and the nitro group, along with the acetylamino group. The acidic hydrogen may be 10 contained in any acidradical such as the carboxylic, sulphonics; etc. 3 e 1 The method by' which the compounds are prepared,-together with thenumberof compounds I have investigated, shows that-all of the acids of the generic group heretofore defined maybe emv ployed to produce my novel aromatic mercury salts. The compounds so" prepared have in greater or lesser degre, but always in a-relatively high degree, antiseptic and germicidal proper- 20 ties. I, therefore, regardmyinvention-as generic to andi'ncludingthe entire group of aromatic mercury-saltsof acetylamino substituted acids of the above defined type.

The general'methodof producing these salts 25 consists in reacting together an acetylamino sub-V stitutedacid and a. compound containing an aromatic mercury radical of -the above defined type. A-liquid reacting medium is employed. The compoundresultin'gfrom the reactionis usually relab tively insoluble as compared 'with the reacting components and upon its precipitation-'may be filtered, washed-anddried. The aromatic mer-' cury compound I prefer: is thehydroxide becausein 'the reaction of theh'ydroxide with the acid; 5

water islthe only other product produced and the resulting aromatic mercury saltmay be easily purified. My novel compounds may also be prepared by employing'a soluble aromatic mercury salt, for example theacetate or lactate ina re- 40 actionxwith the acetylamino substituted-acid. The .aromati'c mercury salts formed during the reaction are oi-a relatively low solubility as compared with the acetylamino-' substituted acids and with the aromatic-mercury salts formed dur- 45 ing the reaction Compounds. may also be prepared by reacting an acid derivative, such as an ester or anhydride, with --anaromatic mercury hydroxide to form thecorresponding aromatic mercury salt. Any of these generalmethods'may '50 be employed in producing the compounds comprising this invention. In any of these methods, the substituted acetylamino group or groups do not enter into the reaction. The structure of the compounds'rernains the-same except for the relili placement of the acidic hydrogen or hydrogens by the aromatic mercury group or groups.

Any inert liquid may be used as the medium for carrying out the reaction, inasmuch as its only function is to bring the reacting components together. Water is convenient to use because of its availability. Other solvents are equally as satisfactory, such as alcohol, acetone, benzol, any other inert organic solvent or mixtures of any of these materials with each other or with water. Alcohol is convenient to use because the reacting components are relatively more soluble therein and smaller quantities of solution are necessary forthe preparation of a given amount of the product.

The process may be carried out at any temperature, for example, room temperature and'it is not dependent upon the use of an elevated temperature. In most instances I find, however, that the use of heat facilitates the solution of reacting components and permits the use of solutions of greater concentration.

The reacting materials are generally employed in substantially theoretical quantities. In some cases, if desired, approximately 10% excess of the acid may be employed in order to insure complete conversion of the aromatic mercury compound.

If the acid employed is a polybasic acid, one or more, including all of the acidic hydrogens may be replaced by the aromatic mercury radical. The number of hydrogens replaced is dependent upon the amounts of the reacting components. If less than all of the acidic hydrogens are replaced, the corresponding acid salts will be formed.

7 Mixed salts in which the acidic hydrogens are replaced by different radicals may be prepared and in the case of polybasic acids containing three or more acidic hydrogen atoms, mixed acid salts may be prepared. Mixed salts may be prepared in which different aromatic mercury radicals replace the acidic hydrogen, but the mixed salts may have any positive radical, in particular, alkali metalsyattached to the acid radical along with the aromatic mercury radical. Compounds of the latter type may be prepared by reacting an alkali metal acid salt of an aetylamino acid with the aromatic mercury com. pound, oran alkali metal base may be reacted with the acid along with the aromatic mercury compound.

The following examples are given as illustra-i tive of the preferred method of preparing the compounds and as illustrative of representative organic mercury compounds falling within the' generic class heretofore described as constitut-t ing my invention:

Example I Example II 10.74 grams of m-acetylamino benzoic, acid. is. dissolved in 5000. of alcohol andto this solution is added 500 cc. of alcohol in which is dis solved 17.64 grams of phenylmercury hydroxide. The solution is concentrated to one-half its original volume and crystals separate. The mixture is filtered and the precipitate is recrystallized from alcohol. The product comprises light brown crystals whichhave a melting point of 190.5- 191 C.; the product is the compound phenylmercury m-acetylamino benzoate.

Example III 10.74 grams of p-acetylamino benzoic acid is dissolved in 50 cc. of alcohol and to the solution is added 17.64 grams of phenylmercury hydroxide dissolved in 300 cc. of alcohol. The solution is I concentrated to one-half its original volume and light brown shiny crystals precipitate. These are removed by filtration and recrystallized from alcohol. The product has a melting point of 191.5-192 C. and is the compound phenylmercury p-acetylamino benzoate.

Example IV 13.74 grams of 'acetylamino naphthoic acid is dissolved in 200 cc. of alcohol. To the solution is added 500 cc. of alcohol containing 17.64 grams of phenylmercury hydroxide. The material is concentrated to one-half its original volume; and crystals separate which are removed by filtration and are washed with alcohol. The product is recrystallized from alcohol and'forms brownish shining crystals; it has a melting point of 204- 206 C. and is the compound phenylmercury acetylamino naphthoate.

E I ample V 5.22 grams of acetyl asparagine (acetylamino succinamic acid) is dissolved in cc. of alcohol and filtered into 500 cc. of an alcoholic solution containing 8.82 grams of'phenylmercury hydroxide. The solution is concentrated to three-fourths of its; original volume and set aside and allowed to stand. A white crystallinemass separates which is removed by filtration, washed well with alcohol, and dried; It is. then recrystallized from alcohol. Uponheating the material it decomposes at 151 C.; it is the compound phenylmercury acetylamino succinamate. I

Example VI 17 .64 grams of phenylmercury hydroxide is dissolved in 500 cc. of alcohol and to this solution is added 10.38 grams of a-acetylamino caproic acid dissolved in 200 cc. of alcohol. The .materialis concentrated to a small volume and a reddish oil separates. This is treated with 200 cc. of alcohol, heated to boiling, and allowed to cool. The supernatant liquid is decanted and white crystals 7 separate therefrom. The product has a melting point of 138 C. and is the compound phenylmercury a-acetylamino caproate.

Example VII 12.48 grams of p-acetylamino phenyl glycine (p-acetylamino phenyl aminoacetic acid) is dissolved in 300 cc. of alcohol and added to 17.64

grams of phenylmercury hydroxide dissolved in 500cc. of alcohol. No precipitate forms on the. addition and the solution is filtered and concentrated to three-fourths of its original volume. Grayish nodules, separate which are removed by filtration, washed, and recrystallized from alcohol. The product decomposed at 171 C., and

is the compound phenylmercury p-acetylamino phenyl aminoagetate. I.

Example VIII 29.40 grams of phenylmercury hydroxide is added to 500 cc. of alcohol. When the solution is complete, the solution is filtered and to the filtrate is added 10.25 grams of 3-acetylamino phthalic anhydride. The mixture is refluxed on a steam bath and allowed to cool. The precipitate which forms is separated by filtration and recrystallized from alcohol. It has a melting. point of 243-244" C., and is the compound diphenylmercury 3-acetylamino phthalate.

Example IX 17.64 grams of phenylmercury hydroxide is dissolved in 500 cc. of alcohol and to the solution is added an alcoholic solution containing 14.16 grams of 3, 5-diacetylamino benzoic acid. .The mixture is concentrated and a blackish gray precipitate separates which. is recrystallized from alcohol to yield light yellow crystals which do not melt when heated up to 220 C.; the product is the compound phenylmercury 3, 5-diacetylamino benzoate.

The diacetylamino benzoic acid may be prepared, if desired, by treating 16.02 grams of diacetylamino benzoic acid dihydrochloride with 4.8 grams of sodium hydroxide in order to neutralize the two hydrochloride groups.

Example X 17.58 grams of 2, 4, G-triacetylamino benzoic acid is dissolved in 200 cc. of alcohol. The solution is then added to 17.64 grams of phenylmercury hydroxide dissolved in 500 cc. of alcohol. The solution is concentrated and a light yellow crystalline material which separates is removed and recrystallized from alcohol. It has a meltingpoint of 177-178 C. and is the compound phenylmercury 2, 4, G-triacetylamino benzoate.

From the description of the specific examples, it will be readily apparent to one skilled in the art how other members of the above identified group may be reacted with an aromatic mercury compound to produce the other mercury compounds of analogous structure which are within the scope of my invention.

The compounds produced as above described are characterized by extraordinarily high potency as antiseptics and germicides. Tests in accordance with Circular 198, of the U. S. Dept. of Agriculture, described as F. D. A. method clearly indicate this excellence.

Thus, after an exposure of minutes aqueous solutions of phenylmercury acetyl anthranilate and phenylmercury 2, 4, 6-triacetylamino benzoate killed standard cultures of Eberthella typhz' (typhoid bacillus) at 37 C. in dilutions as great as 1:100,000 and 1:110,000 respectively. When tested against Staphylococcus aureus by the same method and at the same temperature the latter compound killed this organism after a 15 minute exposure in a dilution of 1 :20,000.

In addition to their germicidal properties, all of these compounds are characterized by relatively low toxicity. Because of these properties it is possible to use them in extreme dilutions and in many situations where known germicides, because of toxic or other undesirable properties, cannot be employed. They may be used externally and locally and in some cases administered internally with satisfactory results from the germicidal standpoint and without harmful effect.

The compounds retain their germicidal activity when incorporated in soap and various menstr ms employed i preparin e mi o po it ons.

When these new compounds are to be used directly as germicides they may be employed in aqueous or other solutions or they may be formed into various preparations such as mouth washes, tooth pastes, soaps, ointments, etc.

I claim:

1. An organic mercury compound having the general formula (RHg) 1R1, in. which R represents an aromatic structure to a carbon atom of which the mercury is directly attached and in which none of the carbon atoms has direct linkage with any element other than hydrogen, 'carbon and mercury; in which R1 represents an acetylamino substituted carboxylic acid radical that is linked to the RHg. group through replacement of carboxyl hydrogen; and in which a represents the number of RHg groups in the compound and is an integer of at least, one and not more than the number of carboxyl groups n the a i R1,

2. An organic mercury compounds having the general formula (RI-Ig).R1, in which R represents an aromatic structure to a carbon atom of which the mercury is directly attached and in which none of the carbon atoms has direct linkage with any element other than hydrogen, carbon and mercury; in which R1 represents an acetylamino substituted aromatic carboxylic acid radical that is linked to the RHg group through replacement of carboxyl hydrogen; and in which :1: represents the number of RHg groups in the compound and is an integer of at least one and not more than the number of carboxyl groups in the radical R1.

3. An organic mercury compound having the general formula (RHg):c-Rl, in which R represents an aromatic structure to a carbon atom of which the mercury is directly attached and in which none of the carbon atoms has direct linkage with any element other than hydrogen, carbon and mercury; in which R1 represents an acetylamino substituted mononuclear aromatic carboxylic acid radical that is linked to the RHg group through replacement of carboxyl hydrogen; and in which :1: represents the number of RHg groups in the compound and is an integer of at least one and not more than the number of carboxyl groups in the radical R1.

4. An organic mercury compound having the general formula RHgRr, in which R represents an aromatic structure to a carbon atom of which the mercury is directly attached and in which none of the carbon atoms has direct linkage with any element other than hydrogen, carbon and mercury; and in which R1 represents an acetylamino substituted benzoic acid radical that is linked to the RHg group through replacement of v carboxyl hydrogen.

5. An organic mercury compound having the general formula (RHg).R1, in which R represents an aromatic structure to a carbon atom of which the mercury is directly attached and in which none of the carbon atoms has direct linkage with any element other than hydrogen, carbon and mercury; in which R1 represents an acetylamino substituted aliphatic carboxylic acid radical that is linked to the RHg group through replacement of carboxyl hydrogen; and in which :1: represents the number of RHg groups in the compound and is an integer of at least one and not more than the number of carboxyl groups in the radical R1.

' 6. An organic mercury compound having the general formula (C6H5Hg)z.R1,in which R1 represents an acetylamino substituted carboxylic acid radical that is linked to the C6H5Hg group -throughreplacement of carboxyl hydrogen; and in which a: represents the number of CsHsHg groups in the compound and is an integer of at least one and not more than the number of carboxyl groups in the radical Rn I '7. An organic mercury compound having-the carboxyl hydrogen; and. in which :1: represents the number of CsHsHg' groups in the compound and is an integer. of'at least one and not'more than the number of carboxyl groups in the radical R1. V r 9. An organic mercury compound having the general formula CeH5Hg.R1, in which R1 represents an acetylaminosubstituted'benzoic acid radical. that is linked to the CsI-I5Hg group throughthe replacement of carboxyl hydrogen.

10. An organicmercury compound having the general formula C6H5Hg.R1, in which R1 repreresents an a'cetylamino substituted aliphatic carboxylic acid radical that is linked to the CeHsHg group through the replacement of carboxyl hydrogen. f

11. Phenylmercury acetyl anthranilate.

12. Ph-e nylmercury 2,4,6-triacetylamino benzoate.

11 3. Phenylinercury acetylamino succinamate.

CARL N. ANDERSEN. 

